Assessment of lytic therapy effect in patients with intermediate‐high risk pulmonary embolism for prevention of chronic thromboembolic pulmonary hypertension: A randomized, double‐blind trial

Abstract Background and Aims This study aims to compare the effectiveness of thrombolytic therapy and anticoagulation in preventing chronic thromboembolic pulmonary hypertension (CTEPH). Method A total of 60 patients with intermediate‐high risk pulmonary embolism (PE) were randomly assigned to receive either thrombolytic therapy (n = 30) or anticoagulation (n = 30). Results Echocardiographic assessments demonstrated no significant differences between the two treatment approaches in terms of right ventricular size (RVS) (on discharge in thrombolytic group: 31.17 ± 3.43 vs. anticoagulant group: 32.73 ± 5.27, p = 0.912), tricuspid annular plane systolic excursion (TAPSE) (on discharge in thrombolytic group: 17.66 ± 2.39 vs. anticoagulant group: 16.73 ± 2.93, p = 0.290), and systolic pulmonary artery pressure (SPAP) (on discharge in thrombolytic group: 32.93 ± 9.73 vs. anticoagulant group: 34.46 ± 9.30, p = 0.840). However, significant changes were observed in all assessed parameters within each treatment group (p < 0.001). The 6‐month follow‐up showed no significant difference between the two groups in terms of CTEPH incidence (p = 0.781) or functional class of the patients (p = 0.135). Conclusion Based on the findings of this study, neither thrombolytic therapy nor anticoagulation demonstrated superiority over the other in reducing adverse outcomes associated with intermediate‐high risk PE, including right ventricular size, SPAP, TAPSE, or CTEPH.


| INTRODUCTION
Pulmonary embolism (PE) is a potentially fatal condition that may lead to early mortality in the acute phase; however, the survivors may face chronic adverse events.Residual thrombi and microscopic vasculopathy subsequent to acute PE episodes are recognized factors contributing to the development of a life-threatening condition that is known as chronic thromboembolic pulmonary hypertension (CTEPH). 1,2though approximately a quarter of patients diagnosed with CTEPH have no confirmed history of PE, CTEPH is the most critical long-term complication of PE that carries significant morbidity and mortality. 3,4Previously, CTEPH was considered a rare postpulmonary event with an incidence rate of 0.1%-0.5% in PE survivors. 5[7] Understanding the process of CTEPH development following an acute PE, incidence, and the associated risk factors provides an improved view for the early diagnosis and prophylaxis of the patients at increased risk.][9][10] The effect of the management of an acute PE and CTEPH has not been well-documented.
Anticoagulation is the primary management for acute submassive PE that prevents future embolic events recurrence, mainly fatal PE with risk of early death.Nevertheless, pulmonary perfusion restoration can be achieved by thrombolytic therapy.Besides, this approach decreases the pressure and resistance of the pulmonary circulation and can cause right ventricular function improvement. 11cording to the guidelines, thrombolytics are the first-line treatment among hemodynamically unstable massive PE patients, while those with submassive PE without hypotension require close observation, and thrombolytic can be administered if they develop cardiopulmonary deterioration.Hence, up until now, there is no strict indication for thrombolytic treatment rather than heparin in submassive PE. 12 Accordingly, the current study, for the first time, aims to evaluate the effect of thrombolytic therapy versus anticoagulation for the prevention of adverse PE-related events, CTEPH in particular.The patients with confirmed Intermediate-high risk PTE 13 diagnosed by an expert cardiologist without a history of previous PTE were included in the study.presence of any past medical history (e.g., COPD, significant valvular heart disease), absolute contraindications to fibrinolytic therapy (such as active bleeding, history of intracranial hemorrhage [ICH] or ischemic stroke in the past 6 months), and severe systematic disorders (e.g., Sepsis) were defined as the unmet criteria.The patients who withdrew the medication or were obliged to cease/alter the treatment because of severe adverse effects and those whose international normalized ratio (INR) was less than the target therapeutic range in over 70% of the assessments were excluded.

| Randomization and blinding
The study has been conducted on all the patients who met the criteria.The patients were randomly assigned into one of the groups using Random Allocation Software by which each patient was provided with a particular number allocated him/her to one of the groups.The patients and cardiologists assessing cardiac function were blinded to whether patients received Alteplase or only anticoagulants for PTE management.
The first group was primarily treated with 100 mg alteplase infusion over 2 h, considering a response to the treatment.The patients allocated to the anticoagulant group received a intravenous infusion mirroring the volume and visual characteristics of Alteplase (utilized as a placebo).
Standard anticoagulant therapy, defining as 80 IU/kg bolus dose of heparin followed by 18 IU/h infusions or enoxaparin 1 mg/kg BD was administered for the second group.
Both groups initiated bridging therapy within 2 days after PTE incidence with oral anticoagulants (warfarin 5 mg), and intravenous treatment was ceased by achieving therapeutic levels of INR.
Afterward, oral anticoagulation was continued for 6 months.INR level was assessed every 2-3 days, and then weekly for 2-3 weeks, until achievement of the desired range of 2-3.Afterward, INR was checked monthly.

| Outcomes
The primary outcome of this study was to compare the effect of each treatment to prevent CTEPH incidence.Accordingly, the first step in the management of the patients before the medications was to perform echocardiography to assess the pulmonary pressure at study initiation.Other echocardiographs were performed at discharge and by 6 months after PTE incidence.All the echocardiographs were done by an expert echocardiography subspecialist, and CTEPH diagnosis was confirm by V/Q pulmonary scan.Secondary endpoints include Besides, the patients' age, gender, risk factor for PTE incidence, oral anticoagulant medication, intervention associated complications, length of hospital stays, and inferior vena cava (IVC) filter implementation were entered into the study checklist.They were also asked about their capability to perform daily chores and categorized according to the New York Heart Association classification.Bleeding was considered as major if it was ICH, required transfusions or intervention for hemodynamic deterioration.Other bleeding episodes considered as minor bleeding (e.g., hematuria, epistaxis).

| Statistical analysis
The obtained data were entered into the Statistical Package for Social Sciences (SPSS Inc.) version 24.Descriptive data were presented in mean, standard deviation, percentages, and absolute numbers.To compare the qualitative data, chi-square test and the quantitative data, an independent t-test (or Mann-Whitney U-test if the data distribution was non-normal) was applied.Paired t-test and a Wilcoxon test were administered.Logistic regression test was used to assess the chance of CTEPH incidence by each of the interventions.A p-value of less than 0.05 was considered as a significant level.size (p = 0.912), TAPSE (p = 0.290), and SPAP (p = 0.840).However, significant alterations were noted in all the parameters assessed in each of the groups (p < 0.001) (Table 2).Table 3 compares the severity of right ventricular enlargement and the severity of SPAP abnormality after applying each of the medications.According to this table, both the approaches led to significant improvement in the severity of RV enlargement (p < 0.001) and SAPS abnormality (p < 0.001); nevertheless, they did not statistically differ between the two treatment groups (p > 0.05).

| RESULTS
The 6-month follow-up assessment of the studied patients revealed an insignificant difference between the two groups regarding CTEPH incidence (10 patients in anticoagulant therapy group, 9 patients in thrombolytic, p = 0.781) and the patients' function class (p = 0.135) (Table 4).
The comparison of intervention-associated complications revealed an insignificant difference between the two groups (p = 0.103).The complications in the thrombolytic treated group included 5 minor bleeding (2 epistaxis, 1 cutaneous hematoma, 2 hematuria) and ICH (1 patient), while only one patient in the anticoagulant therapy group presented heparin-induced thrombocytopenia.No occurrences of in-hospital mortality or hemodynamic instability were noted within our patient.The length of hospital stay was higher among the patients treated with anticoagulant (p = 0.002), while those who were treated with alteplase required more IVC filter implementation (p = 0.0.037)(Table 5).

| DISCUSSION
Previous studies in the literature have progressively demonstrated that thrombolytic agents are capable of dissolving the pulmonary emboli that in turn leads to the improvement of pulmonary perfusion and right ventricular function.Nevertheless, this approach is recommended for the management of massive PEs only. 14,15wever, the efficacy of these agents for Intermediate-high risk PEs has not been well-documented.On the other hand, the administration of these agents should outweigh the risks of thrombolytic use, bleeding in particular. 16e current study tried to assess the efficacy of thrombolytic therapy versus anticoagulant agents for the prevention of PE-related adverse outcomes in both in-hospital and short-term follow-up of 6-month evaluations.Accordingly, we found that none of the administered therapeutic approaches was superior over the other one in terms of CTEPH incidence, right ventricular size, TAPSE, SPAP and the patients' function class.However, the requirement for IVC filter implementation was higher among those who were treated with thrombolytic.
8][19] Thrombolytics are associated with an increased probability of nonmajor bleeding, but major bleedings have been increased insignificantly 20 ; however, Chen and colleagues have presented a twofolds increase in the risk of major bleedings by thrombolytic agents use.Therefore, they ignited a hypothesis regarding the administration of these agents in low doses. 20 the present study all of the patients, regardless of the therapeutic approach had abnormal SPAP on their hospital admission, while significant improvement was notified on-discharge in both groups.Nevertheless, the comparison of the groups revealed an insignificant difference.This finding is in contrast with the study conducted by Ahmed et al. 2 in Egypt, in which those treated with T A B L E 1 The demographic and medical characteristics of the studied population.33% of patients on thrombolytic therapy presented with persistent reduction in their function class. 23The observed CTEPH incidence in our study was higher than reported in some existing literature.This variance could potentially be attributed to diverse regional, racial, and ethnic factors.We hypothesize that the earlier assessment at 6 months, in contrast to the more commonly cited 2-year period, may contribute to this disparity.Furthermore, we concur that the immediate postanticoagulation phase could result in temporary perfusion defects on V/Q pulmonary scans, which might resolve with extended anticoagulation.Additionally, our findings align with studies that have indicated a higher incidence of CTEPH when diagnosed without right heart catheterization, offering further justification for our results. 22

| Limitation
Although we tried our best to enhance the quality of this study, several limitations exist.Our sample size was relatively small, which might affect the generalization of our findings.Subsequently, a more extensive sample size is imperative to effectively consolidate and conclusively expound upon the findings.We followed the patients for 6 months which might be relatively short for an accurate assessment of the effectiveness of our intervention or the probable occurrence of adverse events.

| CONCLUSION
According to the findings of this study, none of the thrombolytic therapy or anticoagulants was superior over the other to reduce the adverse outcomes of Intermediate-high risk PE, including right The follow-up echocardiography of the studied population.
This is a double-blinded randomized clinical trial (RCT) study, includes those with Intermediate-high risk PE admitted from April 2018 to January 2022.The Ethics Committee approved the study protocol based on code number "IR.MUI.MED.REC.1399.281".Moreover, it has been registered into the Iranian Registry of Clinical Trials (IRCT20190301042873N1).The study protocol was explained to the patients (their legal guardians), they were reassured regarding the confidentiality of the personal information and signed written consent.

Figure 1
Figure 1 demonstrates the CONSORT flow diagram of the study population.The current study has been conducted on 60 patients with Intermediate-high risk PTE who were equally assigned into two groups of thrombolytic (n = 30) or anticoagulant (n = 30) therapy.The mean age ± standard deviation of the studied group was 58.5 ± 11.55 years which were predominantly consisted of males (n = 39, 65%).Both groups were similar in terms of age (p: 0.619) and gender distribution (p = 0.176).Besides, both were similar in terms of risk factors for PTE incidence and the administered oral anticoagulant medications (p > 0.05).Detailed information is demonstrated in Table1.Echocardiographic assessments revealed insignificant differences between the two therapeutic approaches regarding right ventricular The echocardiographic characteristics of the studied population.The comparison of echocardiographic dysfunctions severity in the studied groups.
17rombolytic agents presented an statistically significant decrease in their SPAP.Similarly, the other study by Sharifi and colleagues who evaluated anticoagulant therapy alone or in combination with alteplase for the management of Intermediate-high risk PE, stated that SPAP measured 48 h after admission was remarkably lower among those who received thrombolytic agents.17Furthermore,Fusillo et al.21 compared these two treatments in 72 patients (35 ones treated with heparin and the remained ones managed by thrombolysis) and declared significant early improvement of mean pulmonary artery pressure in the thrombolytic-treated than in the heparin group.Right ventricular dysfunction and TAPSE were the other two aspects assessed in our study.We observed significant improvement in both parameters by on-discharge assessments, but no difference was T A B L E 2 Abbreviations: RVF, right ventricular function; SPAP, systolic pulmonary artery pressure; TAPSE, tricuspid annular plane systolic excursion.a Paired t-test. b ndependent t-test. T  B L E 3 incidence of CTEPH or by the assessment of their function class within 6 months after Intermediate-high risk PE.Konstantinides et al. assessed the effects of thrombolytic therapy, tenecteplase, versus placebo on longterm PE adverse events, they reported CTEPH in 2.1% of the cases versus 3.2% in the placebo group with insignificant difference; however, The comparison of complications.size, SPAP, TAPSE, or CTEPH.It is imperative to note that these conclusions are preliminary and further investigation on a larger scale is necessary to validate these findings.The conclusions drawn from the study are merely hypothesis-generating.
Abbreviation: IVC, inferior vena cava.a Fisher's exact test.b Independent t-test.c Fisher's exact test.ventricular